This is a request for and ADAMHA Research Scientist Development Award Level II for Linda S. Crnic, Ph.D. I propose to investigate the possibility that virus infections and the immune response to infections can produce specific behavioral pathology. We have shown that neonatal mice infected with a mutant herpes simplex type 1 virus were hyperactive and had difficulty inhibiting behavior, but could perform a complex spatial learning task. The current proposal involves: 1. further determination of the similarities between of the behavioral effects of the virus and behaviors characteristic of human hyperactivity: 2. elucidation the neural damage produced by the virus and the neural basis for the behavioral changes; 3. determination of the characteristics of the virus and how they account for the neural and behavioral effects. Behavioral measures will determine whether the mice have a global deficit in inhibition of behavior, difficulty maintaining attention, whether they are distractible and explore novel environments in a pattern similar to hyperactive children, whether they perseverate in exploratory tasks, whether they have motor deficits, whether their sleep and circadian rhythms are altered, and whether their food and water intake and response to deprivation is normal. Antiviral drugs will be ueed to limit infection of the brain to determine the role of various brain sites in the behavioral effects. Cells infected will be identified with in situ hybridization and the effects of infection upon neurotransmitter levels determined. Pharmacologic manipulations will be used to pin down the causes of the behavioral changes. We will ascertain whether the low level of expression of viral thymidine kinase determines its virulence and neurotropism. We will test whether a more virulent subset of the injected virus grows in the brain by examining virus retrieved from brain. The role of neural versus non-neural infection in behavioral effects will be explored by looking for peripheral infection and separately both peripheral and neural infection. The role of the immune response in determining the effects of the virus will be explored by preventing the immune response. Whether the virus establishes a latent infection, and whether latent infection alters neural function will be determined.
